Chronic alcohol intake interferes with the onset and progression of liver regeneration after tissue damage, which is thought to contribute to the development of alcoholic liver disease. Our proposed studies will examine how the transcriptional regulatory network response after partial hepatectomy in the rat is affected by chronic alcohol intake. We will use a combination of experimental analysis of gene expression and transcription factor activity changes and computational modeling analysis to evaluate the impact on the transcriptional regulatory network that drive the regenerative response after partial hepatectomy in the rat. Our analysis will involve the following aims: (1) to analyze the temporal dynamics of the transcriptional profile derived from global gene expression data obtained from livers of control and chronically ethanol-fed rats, (2) to modulate the transcriptional network by experimental interventions employing in vivo delivery of small interfering RNAs (siRNAs) that target critical mediators and transcription factors and analyze the corresponding changes in the transcriptional network profile, specifically focusing on signals mediated by TNF-1 and the NF-:B network, and (3) developing a computational modeling approach to identify the major positive and negative feedback loops that control the network and drive the regenerative response. This computational analysis will then be used as a predictive tool to drive further experimental work and characterize the nature of the disruption of the response by chronic ethanol intake. We expect that this analysis will be able to provide novel insights that can do justice to the systemic nature of the regulatory network during liver regeneration and the deregulation of this network by the pleiotropic interactions caused by adaptation to long-term ethanol consumption. PUBLIC HEALTH RELEVANCE: The goal of this project is to gain an in-depth understanding of the mechanisms by which chronic ethanol treatment interferes with the regenerative response to liver damage, which is thought to be a critical element in the susceptibility to alcoholic liver disease. This study will combine an experimental and computational modeling analysis of the temporal profile of gene expression changes and the underlying alterations in activity of transcription factors during the course of liver regeneration after partial hepatectomy in chronically ethanol-fed rats and their pair-fed controls.